Posttraumatic stress disorder (PTSD) occurs in some people after exposure to events that cause extreme fear or helplessness. The incidence of war zones worldwide and the prevalence of violence in large urban centers in the U.S., increases the likelihood of exposure to traumatizing events. Of those who survive such events, approximately 10% will develop this debilitating disorder that affects both the individual and thei family. Individual patients can vary in the degree to which they present with the different symptom clusters, such that a one size fits all treatment is often inadequate. This individual variation may be associated with biological risk factors that increase vulnerability to the disorde or impede treatment. While both genes and environment interact to increase an individual's risk of developing PTSD, it is unclear how the underlying neurobiology is shaped by these factors to result in the observed dysregulations. PTSD is marked by impaired cortical control of the limbic system, specifically the amygdala and hippocampus. We have found that one of the hallmark physiological markers associated with PTSD symptom severity is the inability to inhibit the fear response under safe conditions. This phenotype appears to be a robust marker regardless of trauma type, as it is observed in both civilian and combat PTSD populations. The proposed study will capitalize on this observable marker and individual variability among traumatized individuals to investigate the structural and functional neural underpinnings of impaired fear inhibition. By comparing analyses of this physiological phenotype to the DSM defined disorder, the study will use an innovative approach to understand the pathophysiology of PTSD. The use of state-of-the art imaging tools to fine- tune the measurements of size, shape, and function of the brain areas involved in fear inhibition will offer much-needed insight into individual differences in vulnerability to trauma. PUBLIC HEALTH RELEVANCE: Posttraumatic stress disorder (PTSD) is a highly debilitating and complex disorder frequently co-morbid with many medical and psychiatric illnesses. Understanding the neurobiological mechanisms underlying this disorder will provide improved tools for targeting symptoms that are specific to PTSD. The ultimate goal of this application is to combine clinical psychopathology research and basic neuroscience research to inform the development of novel and effective approaches for treating PTSD, particularly in high-risk populations such as low-income, African-Americans.